Diagnosis of fetal alcohol spectrum disorder (FASD) is difficult because information regarding prenatal exposure is often lacking, many affected children do not exhibit the characteristic facial anomalies, and no distinctive behavioral phenotype has been identified. Development of appropriate treatments has been hampered by limited understanding of the pathophysiology of FASD. Since 1999, we have been conducting a prospective, longitudinal study in the Cape Coloured (mixed ancestry) community in Cape Town, South Africa, where there is an exceptionally high incidence of fetal alcohol syndrome (FAS). In a 5-year follow-up of this cohort, we found a remarkably consistent effect of fetal alcohol exposure on eyeblink conditioning, a cerebellar-dependent form of learning whose neural circuitry and alcohol effects have been documented in detail in laboratory animals; not a single child with full FAS met criterion for conditioning, compared with 75% of the non-exposed controls. Thus, we have identified a potential biomarker of alcohol-related CNS impairment. Moreover, because it is well established in early infancy, short-delay EBC may provide an important tool in the early diagnosis of FASD and in the evaluation of the efficacy of intrapartum and early postpartum interventions. In this study we will follow-up our Cape Town cohort of 165 children at 8.5 years and recruit a new prospective cohort of 60 infants (30 heavy exposed, 30 controls) from the same community. The principal aims are to characterize the developmental course of alcohol-related impairment in EBC; to use selected neuroimaging techniques to examine the impact of fetal alcohol exposure on the neural circuitry mediating EBC; and to use neurobehavioral and functional MRI tasks to assess effects on cerebellar- mediated timing, a central element of EBC. Advanced neuroimaging will include high resolution structural MRI to examine the regional pattern of brain hypoplasia and the first whole brain diffusion tensor imaging (DTI) in children with FASD to assess the integrity of white matter tracts. The moderating effects of maternal age, alcohol abuse history, and variants of the ADH1B polymorphism on the child's vulnerability to FASD will also be examined. Public Health Relevance: A better understanding of the effects of fetal alcohol exposure on the EBC cerebellar circuit in childhood and infancy has the potential to advance our understanding of the neuropathology of FASD, to improve the diagnosis and treatment of this disorder, and to enable earlier identification of affected children. [unreadable] [unreadable] [unreadable]